1. Field of the Invention
The present invention generally relates to medical devices having a blood contacting surface which has thromboresistant properties, more particularly, the invention relates to the surface treatment of medical devices with a thromboresistant coating on the surface which is intended for contacting blood and other body fluids where said coating is composed of a chitosan-based membrane incorporating thromboresistant components affecting surface properties.
2. Description of Related Art
A well-recognized problem in the medical community is the development of a thrombus or blood clot or obstruction that forms when any number of devices are used either within the body or within systems wherein blood or other body fluids are contacted or circulated. Such devices include, for example, catheters, vascular grafts, cardiac pacemaker leads, replacement heart valves, sutures, angioplasty devices, and various blood diagnostic, treatment, and storage systems and may be composed of a variety of biomaterials, for example, metals, polymers, and rubbers.
Of special interest are the approximately 350,000 small vessel bypass grafts performed annually in the United States. The saphenous vein is the choice for small vessel replacement but involves many possible limitations and complications; for example, adequate saphenous vein may not be available due to disease or previous usage. Prosthetic grafts made of expanded polytetrafluoroethylene (ePTFE) or Dacron have been used quite successfully for large vessel replacement but almost uniformly fail when used in sizes of less than 6 mm internal diameters. Callow, A. D., Current Status of Vascular Grafts, Surg. Clin. No. Amer. 65, 501 (1982). There is an urgent need for the development of a small vascular prosthesis (about 3-4 mm inside diameter) that exhibit thromboresistance for use in distal extremity bypasses, coronary artery bypasses, and a variety of other vascular access procedures.
The host response to biomaterials at the cellular and molecular level is complex. For example see, Implantation Biology, The Host Response and Biomedical Devices, (Greco, R. S. ed. 1994). The composition of the biomaterial surface appears to play an important role in thrombosis. Thrombosis is initiated by the adsorption of plasma proteins on the biomaterial surface. This adsorption results from, and is dependent upon, the physical and chemical properties of the biomaterial surface. For example, Dacron has been shown to have a greater effect on platelet activation than ePTFE, while ePTFE is known to be a stronger stimulator of fibrous hyperplasia. Deposition of plasma proteins on the biomaterial surface mediates platelet adhesion via platelet surface receptors. Surface morphology and chemical characteristics, for example, smoothness and hydrophilicity, have been shown to enhance low plasma protein adsorptive properties. As a consequence of the decrease in plasma proteins deposited on the surface, less adhesive matrix proteins will be available to mediate platelet binding and activation on the surfaces, thus leading to reduced surface-initiated thrombosis.
A variety of approaches have been attempted to increase the thromboresistance of these surfaces. These approaches include the bonding of heparin, albumin, or polyurethanes to the surface, the seeding of endothelial cells onto the surface, and the pretreatment of platelets with adhesion receptor specific monoclonal antibodies. All of these approaches, however, have had limited success.
The known practice of graft polymerization of monomers onto the substrate to form thromboresistant polymers on the surface of biomaterials has several drawbacks. Graft polymerization can affect the original chemical structure of the coated biomaterial and has the danger of toxic low molecular residues of the toxic monomers, as discussed in U.S. Pat. No. 4,978,481 to Janssen et al. and U.S. Pat. No. 4,311,573 to Mayhan et al. The grafting process can be complicated and expensive, e.g., requiring elaborate chemical treatment of the substrate. For example, U.S. Pat. No. 5,053,048 to Pinchuk teaches the pretreatment of a substrate before grafting a polymer; in U.S. Pat. No. 4,978,481 the substrate is pre-treated with ozone before grafting the monomer; and in U.S. Pat. No. 4,311,573 the substrate is pre-treated with ozonization or high energy ionizing radiation before the graft polymerization.
An alternative approach to graft polymerization which is based on absorption of biopolymers has been described. Malette, et al, Chitosan: A New Hemostatic, Annals of Thoracic Surgery, 36, 55 (1983) examined the effect of soaking large diameter Dacron vascular grafts in an acidic chitosan solution, a deacetylated derivative of arthropod chitin, as related to the leakage of these grafts. Examination of these grafts at 24 hours revealed no rebleeding. The data establishes that chitosan has thrombogenic properties which induced clot formation rendering the vascular grafts impermeable to blood. Similar thrombogenic properties of chitosan were reported by van der Lei, et al., Improved Healing of Microvascular PTFE Prostheses by Induction of a Clot Layer: An Experimental study in Rats, Plastic and Reconstructive Surgery, 84, 960 (1989). In their study ePTFE grafts soaked in a diluted acidic chitosan solution that were implanted into rats were covered with a clot layer, indicative of a highly thrombogenic surface. Both studies demonstrate the thrombogenic properties of chitosan as exhibited by the molecular adsorption of chitosan on the surface of the grafts employed. Neither study reported that the adsorbed chitosan solution formed a distinct coating layer.
In contrast to chitosan's thrombogenic properties, polyvinylalcohol (PVA) has been reported to exhibit non-thrombogenic properties. Miyake et al., New Small-Caliber Antithrombotic Vascular Prosthesis: Experimental Study, Microsurgery, 5, 144 (1984), reported that tubes made of polyvinylalcohol were non-thrombogenic. These tubes, however, were not suitable for anastomosis since they were not durable enough to withstand tearing by suture.
What is needed is a biomaterial with a non-thrombogenic surface suitable for use in vascular grafts having an inside diameter of less than 6 millimeters and an inexpensive, efficient means for providing consistent non-thrombogenic properties to the surface of the biomaterial.
The present invention provides a biomaterial with a thromboresistant coating, and a method for preparing same. The features and advantages of this invention will be clearly understood through a consideration of the following description.